Disparity analysis and prognostic value of pretreatment whole blood Epstein-Barr virus DNA load and Epstein-Barr encoding region status in lymphomas: A retrospective multicenter study in Huaihai Lymphoma Working Group.

Elevated Epstein-Barr virus (EBV) DNA load is common in lymphomas. However, it remains unclear whether the disparity in viral load and its prognostic value in lymphomas are correlated with Epstein-Barr encoding region (EBER) status. In this retrospective multicenter study, we collected the data of pretreatment whole blood EBV DNA (pre-EBV DNA) and EBER status and evaluated their disparity and prognostic values in lymphomas. A total of 454 lymphoma patients from December 2014 to August 2020 were retrospectively retrieved. Mann-Whitney U test, Kruskal-Wallis test and Bonferroni's adjustment were used to explore the disparity of EBV DNA and EBER status in lymphomas. Time-dependent receiver operating characteristic analysis and MaxStat analysis were used to determine optimal cutoff points of pre-EBV DNA load. Univariable and multivariable Cox proportional hazards models were established for the estimation of prognostic factors. The positive rate of EBV DNA in natural killer T-cell lymphoma (NKTL) patients was higher than that in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) patients, and the median positive pre-EBV copy number of NKTL was also higher than that of FL and DLBCL. EBV DNA could clearly distinguish the prognosis of DLBCL, NKTL, HL and peripheral T-cell lymphoma, and the integration of EBER status and EBV DNA could differentiate the prognosis of HL patients. Multivariable results revealed that pre-EBV DNA load had an effect on the prognosis of NKTL, FL and DLBCL. The status of pre-EBV DNA and EBER were disparate. Whole blood pre-EBV DNA predicted the prognosis of lymphomas, and the combination of EBV and EBER status could differentiate the prognosis of HL.

Cell Differentiation Trajectory Predicts Prognosis and Immunotherapeutic Response in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the main type of malignancy in kidney related to glucose metabolism. Primary single cell culture and single cell sequencing are novel research technologies. In this study, we explored the differentiation status of ccRCC cells and its significance in prognosis and immunotherapeutic response through bioinformatics. We characterized distinct differentiation states and differentiation-related genes (DRGs) in ccRCC cells through single cell RNA sequencing (scRNA-seq) analysis. Combined with bulk RNA-seq data, we classified patients into two clusters and found that this classification was closely correlated with patient prognosis and immunotherapeutic responses. Based on machine learning, we identified a prognostic risk model composed of 14 DRGs, including BTG2, CDKN1A, COL6A1, CPM, CYB5D2, FOSB, ID2, ISG15, PLCG2, SECISBP2, SOCS3, TES, ZBTB16, and ZNF704, to predict the survival rate of patients and then constructed a nomogram model integrating clinicopathological characteristics and risk score for clinical practice. In the study of immune checkpoints, we found that patients in the high-risk group had a disposition to get worse prognosis and better effects of immune checkpoint blocking therapies. Finally, we found the expression level of model DRGs was associated with a tumor-immune microenvironment (TIME) pattern and the response of 83 compounds or inhibitors was significantly different in the two risk groups. In a word, our study highlights the potential contribution of cell differentiation in prognosis judgment and immunotherapy response and offers promising therapeutic options for ccRCC patients.

[The applicable study of two models used in the assessment of long-term exposure to food lead].

OBJECTIVE: To compare the results of observed individual means (OIM) model with beta binomial-normal (BBN) model and to apply the two models to assessment of long-term dietary lead exposure. METHODS: Food consumption data were obtained from the National Nutrition and Health Survey conducted in 2002 by 24-hour recall method. Contamination data were derived from the national food contamination monitoring program from 2000 to 2006 and from monitoring data of Customs exports for agricultural products between 2005 and 2006. By multiplying the average consumption of food with the average concentration of contaminant, the OIM model calculated dietary intake per day. By correcting the within-person variation and keeping the between-person variation, the BBN model built dietary intake in the long-term.Using the example of food lead data, the results of two models were compared. RESULTS: The high-end percentile of OIM model was higher than the BBN model in various age groups.In the general population, the dietary intake of OIM model from 25th percentile to 99.9th percentile was between 1.167 and 7.313 µg×kg(-1)×d(-1), and the dietary intake of BBN model with the same percentile range was between 1.193 and 5.729 µg×kg(-1)×d(-1). The median of various groups was similar between the two models. The dietary intakes in the general population of two models were 1.543 and 1.579 µg×kg(-1)×d(-1). CONCLUSION: The high-end percentile of OIM model is more conservative than BBN model in the long-term dietary exposure assessment.

Variety ACEs and risk of developing anxiety, depression, or anxiety-depression co-morbidity: the 2006-2022 UK Biobank data.

Objectives: Adverse childhood experiences (ACEs) and anxiety-depression co-morbidity are attracting widespread attention. Previous studies have shown the relationship between individual psychiatric disorders and ACEs. This study will analyze the correlation between anxiety-depression co-morbidity and different levels of ACEs. Methods: Seven categories of ACE and four classifications of psychiatric disorders were defined in a sample of 126,064 participants identified by the UK Biobank from 2006-2022, and correlations were investigated using logistic regression models. Then, to explore nonlinear relationships, restricted spline models were developed to examine differences in sex and age across cohorts (n = 126,064 for the full cohort and n = 121,934 for the European cohort). Finally, the impact of the category of ACEs on psychiatric disorders was examined. Results: After controlling for confounders, ACEs scores showed dose-dependent relationships with depression, anxiety, anxiety-depression co-morbidity, and at least one (any of the first three outcomes) in all models. ACEs with different scores were significantly positively correlated with the four psychiatric disorders classifications, with the highest odds of anxiety-depression co-morbidity (odds ratio [OR] = 4.87, 95% confidence intervals [CI]: 4.37 ~ 5.43), p = 6.08 × 10-178. In the restricted cubic spline models, the risk was relatively flat for females at ACEs = 0-1 and males at ACEs = 0-2/3 (except in males, where ACEs were associated with a lower risk of anxiety, all other psychiatric disorders had an increased risk of morbidity after risk smoothing). In addition, the risk of having anxiety, depression, anxiety-depression co-morbidity, and at least one of these disorders varies with each category of ACEs. Conclusion: The prevalence of anxiety-depression comorbidity was highest across ACE scores after controlling for confounding factors and had a significant effect on each category of ACEs.

A Novel Prognostic Index Model for Adult Hemophagocytic Lymphohistiocytosis: A Multicenter Retrospective Analysis in China.

Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder with rapid progression and poor survival. Individual treatment strategy is restricted, due to the absence of precise stratification criteria. In this multicenter retrospective study, we aimed to develop a feasible prognostic model for adult HLH in China. A total of 270 newly diagnosed patients of adult HLH were retrieved from the Huaihai Lymphoma Working Group (HHLWG), of whom 184 from 5 medical centers served as derivation cohort, and 86 cases from 3 other centers served as validation cohort. X-Tile program and Maxstat analysis were used to identify optimal cutoff points of continuous variables; univariate and multivariate Cox analyses were used for variable selection, and the Kaplan-Meier curve was used to analyze the value of variables on prognosis. The C-index, Brier Score, and calibration curve were used for model validation. Multivariate analysis showed that age, creatinine, albumin, platelet, lymphocyte ratio, and alanine aminotransferase were independent prognostic factors. By rounding up the hazard ratios from 6 significant variables, a maximum of 9 points was assigned. The final scoring model of HHLWG-HPI was identified with four risk groups: low risk (≤3 pts), low-intermediate risk (4 pts), high-intermediate risk (5-6 pts), and high risk (≥7 pts), with 5-year overall survival rates of 68.5%, 35.2%, 21.3%, and 10.8%, respectively. The C-indexes were 0.796 and 0.758 in the derivation and validation cohorts by using a bootstrap resampling program. In conclusion, the HHLWG-HPI model provides a feasible and accurate stratification system for individualized treatment strategy in adult HLH.

Prognostic values of geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI) in elderly patients with Diffuse Large B-Cell Lymphoma.

Background: Geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI) are associated with prognosis of various malignancies. Although GNRI and PNI indicates prognosis in some clinical settings, the values of GNRI and PNI on the prognosis of geriatric patients with Diffuse Large B-Cell Lymphoma (DLBCL) is unclear. This retrospective analysis aimed to explore the prognostic values of GNRI and PNI in elderly DLBCL patients. Methods: A total of 133 geriatric patients with DLBCL were recruited from Affiliated Hospital of Xuzhou Medical University, and clinicopathological variables were analyzed. X-Tile program, restricted cubic spline (RCS) and time-dependent receiver operating characteristic (ROC) analysis were used to determine optimal cut-off points of GNRI, PNI and other continuous variables; univariate and multivariate Cox proportional hazards analyses were used for variables selection; Kaplan-Meier curve was utilized to analyze the influence of variables on prognosis; log-rank test was performed for difference evaluation between groups. Results: The optimal cut-off points for GNRI and PNI were 106.26 and 47 by using RCS. Multivariate analysis showed that PNI, age, hemoglobin, liver invasion and central nervous system invasion were independent prognostic factors for elderly patients with DLBCL, and PNI was (P = 0.001, HR = 0.413, 95% CI (0.240-0.710) a stronger predictor. Low PNI could predict worse prognosis independently of elderly patients of DLBCL and could re-stratify patients in GCB group, CD5 positive group BCL-2 positive group, and BCL-6 positive group. Conclusions: PNI was an independent adverse factor for elderly DLBCL and patients with low PNI in GCB group, CD5 positive group and BCL-6 positive group were with poor survival.

Risk stratification model based on VEGF and International Prognostic Index accurately identifies low-risk diffuse large B-cell lymphoma patients in the rituximab era.

Vascular endothelial growth factor affects the invasiveness of solid tumors by regulating angiogenesis. However, it is not clear whether VEGF could be used to predict the prognosis of DLBCL in the era of rituximab-based immunotherapy. We conducted a retrospective study to explore response to therapy and the prognostic value of VEGF on DLBCL in the rituximab era. The subjects were 65 patients with a histological diagnosis of DLBCL from the Affiliated Hospital of Xuzhou Medical University. Kaplan-Meier analysis was performed to estimate the cumulative survival rate of patients with different VEGF and IPI levels, and comparisons between groups were made using the log-rank test. DLBCL patients with elevated VEGF were more likely to have extranodal involvement, advanced stage, Myc/Bcl-2 double expression, and a higher Ki-67 score. Elevated VEGF was associated with poor therapeutic response and survival. When patients were divided into low, low-intermediate, high-intermediate and high-risk groups using the V-IPI model based on VEGF and IPI, PFS rates were 94.4, 74.1, 40.6 and 14.8%, respectively. This model better identified low-risk patients than IPI (85.9, 88.9, 37 and 7.8%). Our results demonstrate that VEGF predicts therapeutic response in DLBCL and the V-IPI model accurately predicts PFS of low-risk DLBCL in the rituximab era.

Potential Genes Associated with the Survival of Lung Adenocarcinoma Were Identified by Methylation.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. The purpose of this study is to search for genes related to the prognosis of LUAD through methylation based on a linear mixed model (LMM). METHODS: Gene expression, methylation, and survival data of LUAD patients were downloaded from the TCGA database. Based on the LMM model, the GEMMA algorithm was used to screen the predictive genes related to LUAD survival. The Cox model was used to further screen the predicted genes, and then, protein-protein interaction (PPI) network was constructed. Through the software plugin Cytoscape MCODE 3.8.0, the most closely related genes in the PPI network module were selected for in-depth biological function analysis to further explore the interaction and correlation between genes. RESULTS: We screened out 97 predictive genes from 18,834 genes and eliminated one gene associated with lung squamous cell carcinoma from previous studies, leaving 96 genes. The MCODE and the Kaplan-Meier curve analysis were used to finally identify two genes ASB16 and NEDD4 that are related to the prognosis of LUAD. CONCLUSIONS: The newly identified two genes associated with the prognosis of LUAD may provide a basis for the treatment of patients.

A Variation in the ABCC8 Gene Is Associated with Type 2 Diabetes Mellitus and Repaglinide Efficacy in Chinese Type 2 Diabetes Mellitus Patients.

Objective Previous studies have suggested that variations in the ABCC8 gene may be closely associated with T2DM susceptibility and repaglinide response. However, these results have not been entirely consistent, and there are no related studies in a Chinese population, suggesting the need for further exploration. The current study investigated the associations of the ABCC8 rs1801261 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. Methods A total of 234 T2DM patients and 105 healthy subjects were genotyped for ABCC8 rs1801261 polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. A total of 70 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take 3 mg repaglinide per day (1 mg each time before meals) for 8 consecutive weeks. The pharmacodynamic parameters of repaglinide and biochemical indicators were then determined before and after repaglinide treatment. Results The frequency of ABCC8 rs1801261 allele was higher in T2DM patients than in the control subjects (22.6% vs.11.0%, p<0.01). After repaglinide treatment, T2DM patients carrying genotype CT showed a significantly attenuated efficacy on FPG (p<0.01) and HbA1c (p<0.01) compared with those with genotype CC. Conclusion These results suggested that the ABCC8 rs1801261 polymorphism might influence T2DM susceptibility and the therapeutic effect of repaglinide in Chinese Han T2DM patients. This study was registered in the Chinese Clinical Trial Register on May 14, 2013 (No. ChiCTR-CCC13003536).

LFG-500, a novel synthetic flavonoid, suppresses epithelial-mesenchymal transition in human lung adenocarcinoma cells by inhibiting NLRP3 in inflammatory microenvironment.

Increasing evidence indicates that inflammatory microenvironment facilitates tumor metastasis. Here, we found that LFG-500, a novel synthetic flavonoid, significantly inhibited epithelial-mesenchymal transition (EMT) in human lung adenocarcinoma A549 and H1299 cells co-cultured with LPS-challenged THP-1 cells or cultured in THP-1 cell-derived conditioned medium. Moreover, we found that TNF-α is a direct and decisive factor for promoting EMT and LFG-500 suppressed TNF-α-induced EMT and cell motility. NLRP3 knockdown inactivated NLRP3 inflammasome, which subsequently inhibited EMT and blocked cell migration, indicating that TNF-α-induced EMT requires the NLRP3 inflammasome. LFG-500 inhibited the activation of the NLRP3 inflammasome, thus inhibiting EMT. Moreover, LFG-500 treatment significantly inhibited metastasis in vivo by downregulating NLRP3 expression. Importantly, we found that NLRP3 was highly expressed in high-grade lung adenocarcinoma and that its expression was correlated with lymph node metastasis. NLRP3 and vimentin levels were significantly increased in matched metastatic lymph nodes. Moreover, a significant positive correlation was observed between their levels. Together, these results suggest that LFG-500 markedly suppresses EMT by inhibiting the NLRP3 inflammasome in the inflammatory microenvironment and that NLRP3 is a potential biomarker of lung adenocarcinoma metastasis.

A systematic review on food lead concentration and dietary lead exposure in China.

BACKGROUND: By synthesizing results from primary studies, systematic review can provide empirical information of concerned problems. This study aimed to review the available surveillance data from studies reporting the contamination surveillance of food lead in China. METHODS: Relevant studies were identified by systematically searching Chinese Biological Medicine Database and China National Knowledge Infrastructure using the key term of "lead" for surveillance data published in Chinese between 2006 and 2012. To avoid potential selection bias, all articles were evaluated by two independent reviewers, and the disagreements were resolved by discussion or the third author was asked to arbitrate. RESULTS: Among 269 identified publications on surveillance data of lead in food, 43 articles met the defined inclusion criteria. The food samples were divided into 11 groups (cereal grains and pulses, fish, eggs, vegetables, meat, edible fungi, milk and dairy products, fruits, offal, tea and preserved egg). Surveillance data of publications were reviewed to calculate the weighted mean and rate exceeding maximum levels. Our results indicated that the highest lead concentration was 1.937 mg/kg in tea. The total percentage of samples exceeding the maximum levels was 5.57%. Dietary exposure to lead was assessed by combining the weighted mean concentration of surveillance data with national consumption data in 2002. In this review, dietary intake of lead was 1.232 µg/kg b.w./day. CONCLUSION: Further control measures should be taken to reduce exposure to lead, from both dietary and non-dietary sources.

Dietary exposure and risk assessment to lead of the population of Jiangsu province, China.

The paper's main purpose is to estimate the dietary exposure to lead for the inhabitants of Jiangsu province, China. Lead concentration data were obtained from the national food contamination monitoring programme during 2007-10. Food samples (n = 2077) were collected from 23 food categories in Jiangsu province. Consumption data were derived from Chinese national nutrition and health survey in 2002, which included 3938 inhabitants from 1451 households in Jiangsu province. Concentration data were combined with consumption data to estimate the dietary intake for the inhabitants of 2-6, 7-17 and 18-80 years, respectively. The ß-binomial-normal (BBN) model was used to estimate the long-term intake for the population in Jiangsu province. The distribution of individual margin of exposure (IMoE) was introduced to assess the health effect. Uncertainty of IMoE was quantified by Monte Carlo and bootstrap methods. The mean levels of dietary exposure to lead were estimated at 3.019 µg kg(-1) bw day(-1) for children aged 2-6 years, 2.104 µg kg(-1) bw day(-1) for teenagers aged 7-17 years, and 1.601 µg kg(-1) bw day(-1) for adults aged 18-80 years. The mean intakes for the urban and rural populations were 1.494 and 1.822 µg kg(-1) bw day(-1), respectively. From the 25th to 99.9th percentiles, IMoE was 0.125-2.057 for 2-6 years and 0.473-7.998 for 18-80 years, respectively. The distribution of IMoE could indicate a public health concern on lead for the Chinese population in Jiangsu. Control measures should be taken to reduce lead exposure in Jiangsu province.